There are a number of inherited diseases, which are associated with the gradual accumulation of iron. These include β-thalassaemia major and thalassaemia intermedia. Due to its facile redox chemistry, excess iron in human body often results in irreversible damage to endocrine organs and lethal cardiac toxicity. In humans such excess iron can not be excreted via normal routes, namely, the urine and the bile, and consequently chelation therapy is essential (J. Med. Chem. 1998, 41: 3347-3359; Inorg. Chem. Acta 1999, 291: 238-246).
The objectives of iron-chelation therapy for iron overload are two fold: first, to produce negative iron balance by removing excess body iron; and second, to detoxify the excess iron while, and until, the first objective is achieved (Drug Safety 1997, 17: 407-421). In order to be considered harmless, iron must be fully coordinated. If any of its six coordination sites remain uncoordinated, iron will participate in Fenton reactions, resulting in lipid peroxidation with organelle and cell damage from hydroxyl radicals (Baillieres Clin. Haematol. 1989, 2: 195-256). Therefore, the iron chelator has to be able to form the iron complex with extremely high stability. Specificity of iron binding over other metals (e.g., zinc and copper) is also necessary to avoid chelation of these metals, which are needed for normal physiological activities.
Ideally, an iron chelator should have a low degree of penetration into the central nerve system and should produce a high degree of extraction of iron from hepatic cells, where iron is present in high levels (Drug Safety 1997, 17: 407-421; Acta Haematol. 1996, 95: 6-12). A second constraint of chelator design is that iron must not be redistributed from liver to other parts (e.g., heart and joint) of the body where it may be harmful. This requires that the iron complex be extremely stable. For a chelator to be efficiently absorbed from the gut, the molecular weight of the chelator has to be about 400 Dalton.
There has been considerable interest in the design of orally active iron chelators over the last two decades and many high-affinity iron chelators have been prepared (J. Med. Chem. 1990, 33: 1749-1755; J. Med. Chem. 1993, 36: 2448-2458; J. Med. Chem. 1993, 36: 2448-2458; J. Med. Chem. 1994, 37: 461-466; J. Med. Chem. 1994, 37: 93-98; J. Med. Chem. 1998, 41: 3347-3359; Eur. J. Med. Chem. 1999, 34: 475-485; J. Med. Chem. 2000, 43: 1467-1475, J. Pharm. Pharmacol. 2000, 52: 263-272; Bioorg. Med. Chem. 2001, 9: 563-573; Bioorg. Med. Chem. 2001, 9: 3041-3047; Tetrahedron 2001, 57:3479-3486). As a result, 1,2-dimethyl-3-hydroxypyridin-4-one (DMHP, CP20, Deferiprone) has been selected as the clinical candidate for the treatment of iron overload. One of the problems with such an N-alkyl-3-hydroxypyridin-4-one is the ability of the free ligand and the resulting iron complex to rapidly penetrate cell membranes and other biological barriers (Drug Met. Disp. 1992, 20: 256-261). A second problem is that N-alkyl-3-hydroxypyridin-4-ones are rapidly metabolized by glyceronidation of the 3-hydroxy group, which will lead to disappearance of iron-chelating properties of the molecule. Despite recent developments, there is a continuing need for new iron chelators, which have high binding affinity for iron and are able to accumulate in liver, the major storage organ in iron-overload conditions.
For many years radical scavenging antioxidants have been successfully used to protect synthetic material and food products from degradating process of oxidation (Cosmet. Sci. Technol. Ser. 1997, 16: 159-179). Radical scavengers have been proposed as neuroprotective agents for the treatment of disorders known to involve oxidative stress, such as stroke, tramatic brain injury, spinal cord injury, cerebral tumor, subharrchnoid haemorrage/cerebral vasospam, cerebral ischaemia, stroke, Alzheimers' disease, Huntington's disease, Parkinson's disease, Friedrich ataxia, motor neuron disease or multiple sclerosis. However, the effectiveness of radical scavengers in reducing oxidative stress within living biological environment is often undermined by the continual production of free radicals mediated by iron. Since Fe is involved in the production of toxic free radicals, several radical scavenger-conjugated 3-hydroxy-4-pyridinones have been prepared and studied as potent inhibitors of lipid peroxidation and cell toxicity (J. Med. Chem. 2000, 43: 2779-2782). Some display a superior neuroprotective activity compared to dual administration of the radical scavenger, di-tert-butylphenol, and the iron chelator, Deferiprone, demonstrating the synergistic effect between the radical scavenger and the iron chelator.
Vanadium compounds, in vitro, stimulate glucose uptake and inhibit lipid break down, in a manner remarkably reminiscent of insulin's effect. Vanadium chelates with organic chelators present ways to fine tune the effect of vanadium, thereby minimizing any adverse effects without sacrificing important therapeutic benefits. Many compounds have been proposed as “insulin mimetics”. These include vanadium complexes of pyronates (J. Med. Chem. 1992, 35: 1489-1491; J. Am. Chem. Soc. 1995, 117: 12759-12770; Can. J. Physiol. Pharmacol. 1995, 73: 55-64; Can. J. Physiol. Pharmacol. 1996, 74: 1001-1009; J. Inorg. Biochem. 1997, 68: 109-116;), pyridinates (Transition Metal Chem. 2001, 26: 219-223), picolinates (Inorg. Chem. 1999, 38: 2288-2297), and cycteine ester (Inorg. Chim. Acta 1980, 46: 2288-L119-L125), and have been recently reviewed (J. Chem. Soc., Dalton Trans. 2000, 2885-2892; Coord. Chem. Rev. 2001, 219-221: 1033-1053).
For vanadium to be useful as an orally available insulin mimetic agent, it must be able to cross biological membranes, both for the initial absorption process and intracellular uptake. Therefore, the metal chelate must have low molecular weight, neutral charge, and a fair degree of resistance to hydrolysis. The lipophilicity of the metal chelates must be balanced with its hydrophilicity, and possess adequate thermodynamic stability. As bidentate chelators for the design of vanadium chelates useful as insulin enhancing agents, 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones are exemplary. Both 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones form stable and neutrally charged vanadium chelates, which have an optimal combination of water solubility, reasonable hydrolytic stability, and significant lipophilicity (J. Chem. Soc., Dalton Trans. 2000, 2885-2892; Coord. Chem. Rev. 2001, 219-221: 1033-1053).
N-Alkyl-3-hydroxy-4-pyridinones form very stable six-coordinated gadolinium chelates (Inorg. Chim. Acta 1992, 191: 57-63), potentially useful as MRI contrast agents. They also form very stable Zn(II) and Tin(II) complexes, which are useful in dental care formulations (Polyhedron 2000, 19, 129-135; Inorg. Chem. 2001, 40, 4384-4388). In addition, 67Ga, 111In and 99mTc complexes of N-alkyl-3-hydroxy-4-pyridinones have been studied as potential radiopharmaceuticals either for imaging or for the radiolabeling of white blood cells (Nucl. Med. Biol. 1992, 19: 327-335; Nucl. Med. Biol. 1993, 20, 857-863; Inorg. Chem. 1994, 33, 5607-5679; J. Med. Chem. 1996, 39: 3659-3670; Eur. J. Nucl. Med. 1999, 26: 1400-1406). Other potential applications for substituted 3-hydroxy-4-pyridinones also include their use for the treatment of overload of other metals (e.g., copper, zinc, aluminum and plutonium) present in the body in deleterious amounts, inflammatory disease (J. Biol. Chem. 1996, 271: 7965-7972; Bioorg. Med. Chem. Lett. 2001, 11: 2573-2575), atherosclerotic disease (Neuroreport 1999, 10: 717-725), neoplastic disease, and thrombosis.
UK Patent No. 2 136 807 discloses the use of 3-hydroxy-4-pyridinones for the treatment of iron overload arising from various causes, particularly that arising from pathological conditions such as thalassaemia, sickle cell anaemia, asplatic anaemia, and idiopathic haemochromatosis, often through the treatment of the first three conditions by regular blood transfusions. In addition, 3-hydroxy-4-pyridinones are of interest for the treatment of pathological conditions where there may be an excess of iron deposited at certain sites even though patients do not exhibit a general iron overload.
EP Patent No. EP0335745 A1 discloses a process for preparation of substituted 3-hydroxy-4-pyridinones. EP Patent No. EP0768302A2 and UK Patent No. GB2 269 589A also disclose synthesis of N-substituted 3-hydroxy-4-pyridinones and pharmaceutical compositions containing thereof. The substituent at the N atom is an aliphatic hydrocarbon group.
U.S. Pat. No. 5,256,676 discloses synthesis of N-substituted 3-hydroxy-4-pyridinones and a method for the treatment of a patient having a condition caused by an iron-dependent parasite which comprises administering to that patient a therapeutically effective amount of N-substituted 3-hydroxy-4-pyridinones.
Proposals have been made in EP Patent No. EP 0316279A2 to modify the 3-hydroxy group of the 3-hydroxy-4-pyridinones to provide a pro-drug form, i.e., in the form of a drug which does not itself possess the desired biological activity but which is converted in vivo to a drug which does. UK Patent No. 2 269 589 specifically discloses the use of substituted 3-hydroxy-4-pyridinones as chelating agents for the treatment of iron overload.
International Publication No. WO 98/54138 discloses preparation of 3-hydroxy-4-pyridinones as orally active iron chelators and their pharmaceutical formulations. The substituent at the N atom contains an aliphatic hydrocarbon group substituted by a hydroxy group or a carboxylic acid ester, sulfonic acid ester or a C1-6-alkoxy or C7-10-aralkoxy ether. International Publication No. WO 98/01458 also discloses preparation of N-substituted 3-hydroxy-4-pyridinones as iron(III) chelators. The N-substituents are selected from polyhydroxycarbons, such as saccharides.
UK Patent No. GB2345058A, International Publication No. WO 99/23075 and European patent applications EP1006108A1 and EP1006112A1 disclose preparation of N-substituted hydroxypyridinone derivatives as reactive oxygen species scavengers. The N-substituted hydroxypyridinone derivatives contain both ortho-hydroxypyridinone and oxygenated aryl (including heteroaryl) functionalities, which possess the dual ability to chelate iron and scavenge reactive oxygen species. The N-substituted 3-hydroxy-4-pyridinone derivatives are particularly useful for the treatment of a condition associated with oxidative stress, such as oxidative damage of the central nervous system or an acute or chronic neurological disorder such as tramatic brain injury, spinal cord injury, cerebral tumor, subharrchnoid haemorrage/cerebral vasospam, cerebral ischaemia, stroke (ischaemic or haemorragic), Alzheimers' disease, Huntington's disease, Parkinson's disease, Friedrich ataxia, motor neuron disease or multiple sclerosis.
U.S. Pat. No. 6,046,219 and International Publication Nos. WO 96/22021, WO96/41639, and WO 99/30562 disclose the use of hydroxypyridinone derivatives useful for the treatment of fibroproliferative disorders by inhibiting protein hydroxylation. Inhibitors of protein hydroxylases (including aspartyl/asparaginyl hydroxylase, prolyl 4-hydroxylase, and deoxyhypusine hydroxylase) block the biochemical events that are required for the formation of excessive fibrocellular scar tissue, and therefore have anti-fibroproliferative properties of clinic importance.
U.S. Pat. No. 5,877,210 discloses a conjugate comprising an inhibitor of phosphotyrosine phosphatase covalently conjugated to a specific binding partner for a cell surface receptor found on B cells, wherein the inhibitor of phosphotyrosine phosphatase is a compound comprising a metal chelate of an organic chelator selected from the group consist of (a) keto-enol tautomers with the keto and enol groups on adjacent carbon atoms that form 5-membered chelate ring or (b) beta-diketones in which the two keto groups are separated by one carbon atom, that form a 6-membered chelate ring. The metal chelates disclosed include V(IV), Cu(II) and Ga(III) complexes of hydroxypyridinones, hydroxymates and acetylacetone. The inhibitory activity of 3-hydroxy-4-pyridinones on mammalian tyrosine hydroxylase has also been reported recently (Biochem. Pharmacol. 2001, 61: 285-290).
International Publication No. WO 01/12168 discloses a pharmaceutical composition comprising an iron chelator and another virus-inhibiting compound for the treatment of viral infection, in particular of the human immunodeficiency (HIV). The iron chelator is selected from the group of hydroxamates or hydroxypyridinones while the viral-inhibiting compound is selected from protease inhibitors or reverse transcriptase inhibitors.
U.S. Pat. No. 6,294,152 discloses Fe(III) complexes of 3-hydroxy-4-pyridinones useful as MRI contrast agents. In all the cases, the N-substituent is a simple or substituted alkyl or aryl group.
International Publication No. WO 91/12822 discloses preparation of Fe(III) and Mn(II) complexes of 3-hydroxy-4-pyridinones useful as MRI contrast agents. The substituents on the pyridinone ring are simple alkyl groups substituted with phosphonate or sulfonate groups.
U.S. Pat. Nos. 5,527,790 and 5,866,563 disclose vanadium compositions for the treatment of elevated blood sugar. Vanadium chelates disclosed include those containing hydroxamates, o-heterocycle-substituted phenolates, 3-hydroxy-4-pyrones, and N-substituted 3-hydroxy-4-pyridinates. In all the cases, the N-substituent is a simple or substituted alkyl or aryl group.
U.S. Pat. No. 6,232,340 discloses organovanadium complexes and pharmaceutical compositions containing hydroxyoxovanadium(V), μ-oxo dimeric vanadium(V), and cis-dioxovanadium(V) complexes for the treatment of diseases or disease states, including use as antiproliferative and/or antimetastatic agents.
International Publication No. WO 93/10822 discloses cationic 99mTc(IV) complexes with N-substituted 3-hydroxy-4-pyridinones as diagnostic scintigraphic imaging agents. The N-atom is directly attached to a carbon atom from a simple or substituted alkyl or aryl group.
International Publication No. WO 00/16736 discloses an oral care composition containing antiplaque agents. The antiplaque agents are metal complexes of Cu(II), Zn(II), Sn(II), Fe(II), or Fe(III) with a specific class of cyclic α-hydroxylketones, including 3-hydroxy-4-pyrones.
However, there remains a need for therapeutic agents with enhanced efficacy, solution stability, and optimal combination of lipophilicity and hydrophilicity. This invention is directed towards meeting this need.